AG8 cells, which are highly resistant to hydrogen peroxide, display collateral sensitivity to the combination of hydrogen peroxide and L-histidine.

The results obtained in the present study indicate that AG8 cells, which are highly resistant to H2O2, are not cross-resistant to the combination of H2O2/L-histidine. In fact, once the influence of elevated catalase on the AG8 pheno-type has been circumvented (by treatment of AG8 cells with aminotriazole), AG8 cells display essentially no cross-resistance to the H2O2/L-histidine cocktail while retaining considerable resistance to H2O2 alone (when compared to wild-type AA8 cells). Although H2O2 alone dose not produce DNA double strand breaks (DSBs), this type of lesion was readily detected upon exposure of sensitive or resistant cells to the oxidant in the presence of the amino acid. Interestingly, similar levels of DNA DSBs were detected in AA8 and catalase-depleted AG8 cells. An excellent correlation was found when the cytotoxicity and the level of DNA DSBs obtained in sensitive and resistant cells (with normal or reduced catalase levels) challenged with the cocktail H2O2/L-histidine were compared. This would suggest that DSBs produced on a per cell basis always result in an equal level of toxicity, regardless of the cell type (resistant versus sensitive cell line), the lethality of each of these cell lines being dependent on the number of induced DSBs. In conclusion, the results presented here provide further evidence in support of the hypothesis that cell killing elicited by the combination of H2O2/L-histidine involves a mechanism distinct from that following treatment with H2O2 alone. The fact that H2O2-resistant AG8 cells, which are not cross-resistant to agents promoting cell death via DNA DSB-induction, display collateral sensitivity to the cocktail H2O2/L-histidine, strongly suggests that cell killing triggered by this treatment is mediated by DNA double strand breakage.